RESUMO
A novel alpha7 nAChR agonist, N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide (3a, PHA-709829), has been identified for the potential treatment of cognitive deficits in schizophrenia. The compound shows potent and selective alpha7 in vitro activity, excellent brain penetration, good rat oral bioavailability and robust in vivo efficacy in a rat auditory sensory gating model.
Assuntos
Compostos Azabicíclicos/farmacologia , Agonistas Nicotínicos/farmacologia , Piridinas/farmacologia , Receptores Nicotínicos/efeitos dos fármacos , Animais , Compostos Azabicíclicos/síntese química , Compostos Azabicíclicos/química , Benzamidas/farmacologia , Proteínas Sanguíneas/efeitos dos fármacos , Compostos Bicíclicos com Pontes/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Cães , Relação Dose-Resposta a Droga , Humanos , Camundongos , Microssomos Hepáticos/efeitos dos fármacos , Conformação Molecular , Agonistas Nicotínicos/síntese química , Agonistas Nicotínicos/química , Piridinas/síntese química , Piridinas/química , Quinuclidinas/farmacologia , Ratos , Receptores Muscarínicos/efeitos dos fármacos , Estereoisomerismo , Relação Estrutura-Atividade , Receptor Nicotínico de Acetilcolina alfa7RESUMO
A novel set of azabicyclic aryl amides have been identified as potent and selective agonists of the alpha7 nAChR. A two-pronged approach was taken to improve the potential hERG liability of previously disclosed alpha7 nAChR agonist, PNU-282,987, while maintaining the compound's other desirable pharmacological properties. The first approach involved further exploration of the aryl carboxylic acid fragment of PNU-282,987, while the second approach focused on modification of the azabicyclic amine portion of PNU-282,987. The best compounds from each series are characterized by rapid brain penetration, good oral bioavailability in rat, and demonstrate in vivo efficacy in a rat P50 auditory sensory gating assay. At least one analog from each series (1h, 1o, 2a, 9a, and 18a) shows an improved hERG safety profile over PNU-282,987.
Assuntos
Encéfalo/metabolismo , Desenho de Fármacos , Agonistas Nicotínicos/farmacologia , Receptores Nicotínicos/química , Animais , Bungarotoxinas , Células Cultivadas , Eletrofisiologia , Potenciais Evocados Auditivos/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Ativação do Canal Iônico/efeitos dos fármacos , Estrutura Molecular , Atividade Motora/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Agonistas Nicotínicos/síntese química , Agonistas Nicotínicos/química , Técnicas de Patch-Clamp , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Sinapses/efeitos dos fármacos , Sinapses/fisiologia , Receptor Nicotínico de Acetilcolina alfa7RESUMO
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide (14, PHA-543,613), a novel agonist of the alpha7 neuronal nicotinic acetylcholine receptor (alpha7 nAChR), has been identified as a potential treatment of cognitive deficits in schizophrenia. Compound 14 is a potent and selective alpha7 nAChR agonist with an excellent in vitro profile. The compound is characterized by rapid brain penetration and high oral bioavailability in rat and demonstrates in vivo efficacy in auditory sensory gating and, in an in vivo model to assess cognitive performance, novel object recognition.
Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Transtornos Cognitivos/tratamento farmacológico , Agonistas Nicotínicos/síntese química , Nootrópicos/síntese química , Quinuclidinas/síntese química , Receptores Nicotínicos/metabolismo , Esquizofrenia/tratamento farmacológico , Animais , Disponibilidade Biológica , Encéfalo/metabolismo , Compostos Bicíclicos Heterocíclicos com Pontes/química , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Estabilidade de Medicamentos , Canais de Potássio Éter-A-Go-Go/efeitos dos fármacos , Potenciais Evocados Auditivos/efeitos dos fármacos , Humanos , Técnicas In Vitro , Aprendizagem/efeitos dos fármacos , Masculino , Memória/efeitos dos fármacos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Agonistas Nicotínicos/farmacocinética , Agonistas Nicotínicos/farmacologia , Nootrópicos/farmacocinética , Nootrópicos/farmacologia , Técnicas de Patch-Clamp , Quinuclidinas/química , Quinuclidinas/farmacologia , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Receptores Nicotínicos/fisiologia , Reconhecimento Psicológico/efeitos dos fármacos , Estereoisomerismo , Relação Estrutura-Atividade , Receptor Nicotínico de Acetilcolina alfa7RESUMO
The metabolism and excretion of N-(3R)-1-azabicyclo[2.2.2]oct-3-ylfuro[2,3-c]pyridine-5-carboxamide (1), an agonist of the alpha7 nicotinic acetylcholinergic receptor, were determined in both Sprague-Dawley rats and beagle dogs using [3H]1. Initially, 3-tritio-furanopyridine 1 ([3H]1a) was evaluated in pilot mass balance studies by determining total radioactivity recovery and pharmacokinetics in lyophilized excreta and nonlyophilized plasma, respectively. Lower mass balance and much greater circulatory radioactivity exposures were observed in rats than in dogs, with urinary tritiated water (HTO) only detected in rats. The 133-h half-life in rats, possibly due to very slowly eliminated metabolites, was more likely attributable to HTO formed from [3H]1a because of site-specific chemical and/or metabolic 3H instability, which was confirmed by urinary HTO. In contrast, dog data supported 3H stability within [3H]1a. Conflicting cross-species data with [3H]1a suggested species-specific metabolic fates for 1, requiring a 3H form of 1 resistant to 3H loss in rats. Therefore, tritiation of 1 at its furanopyridine C7, a site predicted to be both chemically and metabolically stable, yielded 7-tritio-N-(3R)-1-azabicyclo[2.2.2]oct-3-ylfuro[2,3-c]pyridine-5-carboxamide ditrifluoroacetate ([3H]1b), which allowed in both species the determination of all excretory pathways, total radioactivity pharmacokinetics, and major excretory and circulatory metabolites with complete radioactivity recovery without HTO generation. Definitive metabolite elucidation for 1 using [3H]1b confirmed the suspected species-dependent metabolic susceptibility for 3H loss from [3H]1a in rats, but not dogs, since the majority of rat metabolites resulted from furanopyridine biotransformation. The described studies explore the evaluation of tritium exchange risk from a mechanistic biotransformation perspective and highlight the need for careful deliberation when considering and designing 3H compounds for radiolabeled metabolism studies.